Studies on formulations in which medicinal effects of a protein drug last for a long period of time have been mainly conducted to develop formulations through a conjugation reaction with a biocompatible biodegradable polymer. The time for which the medicinal effect of the above-described protein drug lasts extends to several weeks according to the shape of a formulation, and an effective medical ingredient to be conjugated. To develop such a formulation, biocompatibility of a polymer which is conjugated with the effective medical ingredient should be considered in addition to maintenance of the medicinal effects of the formulation and an increase in the time for which the medicinal effect lasts. Also, problems such as a decrease in activity of the protein drug caused by conjugation with the polymer should be taken into consideration.
By way of example of the studies on such a formulation, active research to apply to the drug delivery system by conjugating an effective medical ingredient with biocompatible biodegradable polyethylene glycol (PEG) or hyaluronic acid (HA) has been conducted so far.
However, PEG used for a reaction for conjugating PEG with an effective medical ingredient, that is, a PEGylation reaction, is one of representative polymer materials for living organisms approved by the Food and Drug Administration (FDA), but an ‘accelerated blood clearance (ABC)’ phenomenon in which a drug administered into the body disappears more rapidly when a PEG-liposome conjugate used as a drug delivery carrier is repeatedly injected was reported to take place. In the case of interferon alpha (IFNα), which is a protein drug for treating liver diseases, a PEGylated product is actually produced into a once-a-week injection formulation. A PEGylated interferon drug for treating hepatitis C exhibits severe side effects, and thus there are many cases of patients discontinuing their treatment. Also, the interferon drug shows an anti-viral effect of only approximately 50% in patients with CV genotype 1. Therefore, development of new drugs is required. A drug delivery carrier using PEG serves to simply increase a body retention time without exhibiting delivery characteristics into certain tissues, and thus requires a targeting moiety to deliver it into a certain tissue to treat a certain disease.
Meanwhile, when HA is conjugated with an effective medical ingredient, the resulting conjugate may be specifically delivered to tissues of the liver. However, bioconjugation efficiency by the conjugation reaction between the HA and the effective medical ingredient is low, and thus a limit to the bioconjugation efficiency has been shown.
Also, when the polymer such as PEG or HA is conjugated with the protein drug, the polymer may non-specifically react with various reactive groups in an amino acid sequence of a protein to destroy a tertiary structure of the protein, thereby degrading bioactivities of the protein drug.